The Host Defense Group of the Laboratory of Respiratory Biology, Division of Intramural Research, National Institute of Environmental Health Sciences, headed by Michael B. Fessler, MD now enters its second year at the NIEHS since inception. We have increased our staffing to 4 active laboratory members, and expect another 2 postdocs to join the group within the next 2 months. Moreover, we have submitted a project on a competitive intramural Direcors Challenge Program that, if awarded, will provide our Group with resources to hire 2 additional fellows and to extend our macrophage innate immunity work into atherosclerosis applications. Accomplishments include an original manuscript currently under revision for Journal of Immunology that defines novel roles for the nuclear receptor Liver X Receptor in modulation of pulmonary innate immunity, a meeting abstract on similar material in press to be published in the Proceedings of the American Thoracic Society, 2 middle-author collaborative publications (J Immunol, J All Clin Immunol), and an invited peer-reviewed review article on Liver X Receptor under review for Current Signal Transduction Therapy. Additional accomplishments include a 2008 FARE abstract award for Research Fellow Suraj Dhungana, and a successful competitive application to the NIH Office of Rare Diseases to secure supportive funding for an NIEHS-based symposium on lipid raft biology to be chaired by the PI, that will also correspond with his hosting of a Distinguished Lectureship speaker world-renowned in field of raft biology, Kai Simons. Three talks were delivered by the PI at international, national, and regional meetings, respectively, during the last year. In addition, substantial data has been collected on 5 active research projects in the laboratory: 1) characterization of apoplipoprotein A-I as a novel stimulus of innate immunity; 2) characterization of apolipoproteins A-I and E as novel endogenous regulators of pulmonary innate immunity in a murine model of inhaled LPS; 3) proteomic discovery of novel signaling proteins recruited to macrophage lipid rafts in response to LPS (this latter work has led to several targets which are currently undergoing functional validation for a role in the LPS signaling cascade with the use of RNAi in macrophages); and 4) identification of a modulatory role of high-cholesterol diet upon pulmonary innate immunity in a murine model of inhaled LPS. In addition, several mouse strains deficient in selected regulators of cholesterol trafficking have been procured and either rederived and bred, or are currently undergoing rederivation with an eye towards using them as tools to clarify a role for these regulatory targets in pulmonary innate immunity in vivo. Finally, we believe we have identified a novel TLR4 agonist of viral origin that we plan to characterize and validate further pending the hire of a postdoctoral fellow. Presently, 2 new original manuscripts are under preparation.